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  Disease summary:

  
  
  
  
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    Glycogen storage diseases (GSDs) are a group of inherited disorders of glycogen degradation or synthesis. Because glycogen is stored mainly in the liver, skeletal muscle, and heart muscle, the clinical spectrum of the GSDs is defined by involvement of these organs.

    
    
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    Currently, there are 10 well-defined types initially enumerated in order by which the enzymatic defect was identified. As the genetics of the glycogen pathway became clearer, different types of GSD have been grouped together, as is the case with type VIII and X which are now considered part of type VI.

    
    
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    Types 0, I, III, VI, IX, and XI mainly involve the liver, causing hypoglycemia and hepatomegaly. Type IV disease also involves the liver, but typically causes cirrhosis and liver failure in the absence of significant hypoglycemia. Types II, V, and VII mostly affect the muscle. Patients with type II classically have cardiomyopathy and skeletal muscle weakness, whereas muscle pain, fatigue, and exercise intolerance characterize the latter two types.

  
  
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  Hereditary basis:

  
  
  
  
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    Most GSDs follow an autosomal recessive inheritance. Some patients with GSD V who were thought to be manifesting heterozygotes (only one mutation found in the PYGM gene) recently were found to carry a putative mutant allele when studies were performed on the cDNA in skeletal muscle.

    
    
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    GSD type IX is subdivided depending on the affected subunit of the phosphorylase kinase. When the α subunit is affected, this disorder follows an X-linked inheritance, whereas β and γ subunit deficiency follow an autosomal recessive inheritance pattern.

  
  
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  Differential diagnosis:

  
  
  
  
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    The initial approach to diagnosing a GSD is based on the primary presenting feature. For example, patients with hypoglycemia and hepatomegaly should be evaluated for the hepatic GSDs (I, III, VI, IX) whereas patients with myopathy and muscular weakness in the absence of hypoglycemia should be evaluated for the muscular GSDs (II, V, VII).

    
    
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    The differential diagnosis of hypoglycemia is extensive and includes excessive insulin production or poorly controlled diabetes, disorders of cortisol production, and liver disease. The differential diagnosis of hypoglycemia with hepatomegaly is more limited, and includes mitochondrial hepatopathies, congenital disorders of glycosylation, fructose 1,6 bisphosphatase deficiency, Beckwith-Wiedemann syndrome, and fatty acid oxidation defects.

    
    
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    The differential diagnosis of myopathy and hypotonia includes spinal muscular atrophy, mitochondrial or respiratory chain disorders, limb-girdle muscular dystrophy, Duchenne-Becker muscular dystrophy, hypothyroidism, and fatty acid oxidation defects, such as very long chain acyl coenzyme A dehydrogenase (VLCAD).

Diagnostic Criteria

There are no universal diagnostic criteria for the various glycogen storage diseases but the following clinical information should direct the diagnosis:

Clinical Characteristics

GSD type Ia usually presents within the first few months of life with hypoglycemia, hepatomegaly, lactic acidosis (>2.5 mmol/L), hyperuricemia (>5 mg/dL), hyperlipidemia (TGL >250 mg/dL, cholesterol >200 mg/dL) and typical doll-like faces with fat cheeks, protuberant abdomen, and short stature. GSD type Ib has a similar clinical presentation as GSD type Ia but with additional findings, including neutropenia, recurrent bacterial infections, and inflammatory conditions such as inflammatory bowel disease. Individuals with GSD type Ia and 1b usually become hypoglycemic after about 3 hours of fasting. Glucagon or epinephrine does not cause an increase in blood glucose but lactate levels do increase.

GSD type II can vary and be divided into patients with a classic infantile form and a later-onset form. The classic form is characterized by failure to thrive, severe muscle weakness that includes progressive involvement of the respiratory muscles, hypertrophic cardiomyopathy, and death in infancy if untreated. The later-onset phenotype may present during childhood, adolescence, or adulthood with progressive proximal muscle weakness. The most common presentation of later-onset GSD type II is difficulty rising from a sitting position or climbing stairs, although many patients progress to wheelchair dependence and/or dependence on ventilatory support because of respiratory muscle weakness. Generally, they do not have cardiomyopathy. In all forms, serum creatine kinase may be elevated although a normal value cannot exclude the diagnosis since it can be normal in adults.

GSD type III is similar to GSD type I but usually has a later onset in childhood, and is differentiated by a normal glucagon response if performed within 2 hours after a meal. GSD type IIIa adult patients have skeletal muscle involvement with weakness, occasional pain, and increase in creatine kinase. Cardiomyopathy can occur as well. In adulthood, hepatic transaminases (AST/ALT >1000 U/L) increase but the hypoglycemia usually resolves.

GSD type IV has many different liver and neuromuscular presentations, varying with age of onset. In infants and children there is a classic liver form that presents with progressive liver disease and hepatic fibrosis by the age of 18 months, an infantile neuromuscular form with hypotonia, and a juvenile liver and muscular form which may present with cardiomyopathy. In adults there is a mild nonprogressive liver form; patients may have hepatosplenomegaly but generally do not develop cirrhosis. The adult polyglucosan body disease is an allelic form and may present with progressive central and peripheral nervous system dysfunction such as neurogenic bladder, gait difficulties, sensory loss, and mild cognitive dysfunction (executive function).

GSD type V usually presents in the second to third decade of life with exercise intolerance characterized by cramps and fatigue during the first few minutes of any type of exercise and intense sustained exercise (anaerobic). Symptoms are relieved during rest, as the body uses free fatty acids as a source of energy instead of glycogenolysis to release glucose for fuel. Myoglobinuria with consequent acute renal failure can occur following intense exercise and usually is reversible. GSD type V and VII have similar clinical manifestations. In patients with GSD type VII there may be, in addition, a compensated hemolysis with mild indirect hyperbilirubinemia and reticulocytosis due to partial deficit of erythrocyte glycolysis. Hyperuricemia may be more pronounced in GSD type VII.

Individuals with GSD type VI compared to individuals with GSD type I and III resist an even longer fasting period before they have hypoglycemia, and if present it is usually triggered by an intercurrent illness. They have hepatomegaly and their triglycerides, cholesterol, and liver transaminases may be mildly elevated but the creatine kinase, uric acid, and lactic acid are normal. GSD type VI and IX are difficult to differentiate clinically. If a female has the earlier-mentioned manifestations she is more likely to have type VI since the most common form of type IX has an X-linked inheritance pattern.

GSD type XI is rare and presents in infants. Since a glucose and galactose transporter is defective, there is fasting hypoglycemia and postprandial hyperglycemia and hypergalactosemia. Patients have hepatorenal accumulation of glycogen with secondary proximal renal tubule dysfunction although progression to renal failure is uncommon. Other findings include hyperlipidemia, hyperuricemia, osteopenia, with rickets later in life, and cataracts due to the hypergalactosemia.

GSD type 0 is considered to be a glycogen storage disorder because it involves glycogen metabolism and can present with hypoglycemia. However, GSD 0 is a defect in the synthesis of glycogen, leading to decreased hepatic glycogen content. Children may have fasting hypoglycemia but most adults are asymptomatic or have mild symptoms. See Table 93-1 for system involvement of the different GSDs.